PEDAL THE CAUSE-FUNDED RESEARCH

The Siteman Cancer Center Awards

Project: Functional Genomics of Ovarian Cancer MetastasisPrinciple Investigator: Katherine Fuh, M.D.
Description: 65% of women diagnosed with ovarian cancer will die of this disease.
Metastatic ovarian cancer remains an incurable cancer and novel treatments are
urgently needed. By identifying new gene expression of cancers that have metastasized
in the context of how cancers communicate to the supporting tumor microenvironment,
we have a unique opportunity to find biologically relevant genes. We are using cells
from the tumor microenvironment that pancreatic, colorectal and prostate cancers use
to invade and metastasize. Researchers will be able to use the same technique and find
genes that can be translated to other cancers. The discoveries made in these projects
will pave the way for development of additional agents that will not only treat the cancer
but also lead to less toxicity than chemotherapy. This could help change the treatment
of ovarian cancer which has used the same chemotherapy agents for 20 years.

Project: Designing Novel Therapeutic Approaches to Pancreatic Ductal Adenocarcinoma (PDAC)Principle Investigator: William Hawkins, M.D.
Description: Pancreatic cancer is a devastating disease and current therapies have
limited efficacy. Limitations of current therapeutic strategies include a highly
immunosuppressive immune environment, lack of cancer-selective drug delivery, and
inability to target KRAS driven proliferation. The ultimate goal of this Team Science
Award is to improve the survival of patients with pancreatic ductal adenocarcinoma
(PDAC). The immediate goal is to obtain additional preliminary data in support of a
pending PDAC SPORE application. Our near-term goal is to advance four new and
potentially transformative therapeutic approaches into the clinic for evaluation. We
propose to key proof-of-concept preliminary studies that will provide strong support for
the four collaborative patient-oriented projects developing new therapeutic approaches
for PDAC.

Project: Assessment of Functional Status of Estrogen Receptors in Breast Cancer by PETPrinciple Investigator: Farrokh Dehdashti, M.D.
Description: The majority of patients with breast cancer are tested for
presence of receptors in their tumor tissue from biopsy to see if their disease is sensitive to different
hormones such as estrogen and progesterone. Once tested, they are classified as being estrogen-receptor
positive (ER+), progesterone-receptor positive (PgR+), or both. Prior research has shown that patients
with hormone positive disease usually have slower growing tumors and respond well to endocrine therapies (ET),
which is considered a less toxic form of treatment when compared to chemotherapy. There is no test to separate
patients with ER+ breast cancer who respond to ET from patients with ER+ breast cancer who do not respond to ET.
A test which is non-invasive and able to characterize (whether tumor has receptors and whether the receptors are
functional) the entire tumor in a single image is needed. Such a test would aid doctors in determining the best
possible treatment for breast cancer patients. Positive results from this project could ultimately lead to
individualized treatment to prevent unnecessary treatment for patients in the near future.

Project: FDOPA-PET/MRI for the Pre-operative Evaluation of GliomasPrinciple Investigator: Jonathan McConathy, M.D., Ph.D.
Description: The clinical outcome of patients with brain tumors is variable; some patients
survive for many years while others succumb rapidly to the disease. Surgery is an important treatment for
brain tumors. Complete or near-complete removal of brain tumors increases the chances of survival. We propose
to combine MRI with metabolic imaging to better define tumor borders prior to surgery. If effective, our goal
is to make FDOPA-PET/MRI routinely available to our brain tumor patients and to the physicians caring for them
in order to improve surgical outcomes and identify patients with aggressive brain tumors needing urgent therapy.

Project: Immune-Based Therapies for AMLPrinciple Investigator: John DiPersio, M.D., Ph.D.
Description: In this application we will continue to develop and test in humans for the first
time novel immune-based therapies and cellular therapies for the treatment of acute myelogenous leukemia (AML).
Approximately 60-80% of patients with AML with either relapse or have disease that is refractory to initial
chemotherapy. We will generate and test in the laboratory and in first-in-human clinical trials novel retargeting
agents (small proteins), and will modify and optimize these agents so that natural killer (NK) and cytotoxic T
lymphocyte effector cells more effectively kill the AML cancer cells. We will also test a new class of NK cells
for their ability to kill AML cells. Finally, we will attempt to identify novel proteins on the surface of AML
cells for the future development of targeting agents that engage either T cells, NK cells or other immune effector
cells. We believe these new therapeutic approaches will be profoundly effective in AML and pave the way for
development of similar reagents and approaches for the treatment of other malignancies.

This project will enable ECS targeting dozens of genes to assess MRD in nearly all pediatric AML cases with
comparable accuracy to conventional methods, leading to improved genetic diagnostics for pediatric cancer patients.

Validate the criteria established in Aim 2 using approximately 100 pediatric AML remission samples with
diagnostic genome sequencing and MRD status. This new assay will extend the life-saving capability of
MRD to virtually every pediatric AML patient.

Project: Understanding Mechanisms Of Alkylation Chemoresistance In Pediatric GlioblastomaPrinciple Investigator: Nima Mosammaparast, M.D., Ph.D.
Description: Pediatric glioblastoma is an aggressive brain tumor associated with a very poor
prognosis. Commonly used chemotherapeutic drugs for adult glioblastoma are typically not effective in the pediatric
population. The proposed research is aimed at understanding a newly discovered protein complex that regulates
molecular pathways critical for glioblastoma chemotherapy. It is possible that this enzyme complex, called OTUD4,
could be inhibited to improve the response of pediatric glioblastoma to chemotherapy. The proposal aims to expand
significant preliminary data on the OTUD4 pathway to determine whether this pathway could be targeted in pediatric glioblastomas.

The aims of this proposal are:

To determine whether inhibition of a deubiquitinase complex consisting of OTUD4 and USP7/9X promotes sensitivity
to chemotherapy-induced alkylation damage in pediatric glioblastomas, using a preclinical model.

Understanding how tumor cells regulate the proteins responsible for repairing damage induced by chemotherapy
will have broad implications for not only pediatric glioblastoma, but numerous other tumors that are treated with these drugs.

Project: Targeting The Abnormal Chromatin State Of Pediatric Brain TumorsPrinciple Investigator: Joshua Rubin, M.D., Ph.D.; Albert Kim, M.D.,Ph.D.; Kristen Kroll, Ph.D.; and Hiroko Yano, Ph.D.
Description: Despite decades of research on malignant brain tumors in children, an understanding
of the fundamental mechanisms of tumorigenesis and the requirements for effective treatment remains inadequate.
This proposal addresses the hypothesis that malignant brain tumors in children are caused by abnormalities in chromatin-
a complex of DNA and proteins that forms chromosomes. Recent research has shown that mutations in chromatin regulatory
proteins or in histone H3-a protein found in chromatin-are common to malignant brain tumors in children. Understanding
how the chromatin state (also known as "epigenetics") regulates tumor genesis and how it might dictate the therapeutic
response is the focus of this proposal.

The aims of this proposal are to test whether:

A specific pattern of a chromatin modification called histone H3 lysine 27 tri-methylation (H3K27me3) is
associated with a chromatin signature and gene-expression program characteristic of undifferentiated,
therapy-resistant, tumor-initiating cells.

Loss of this H3K27me3 pattern induces a chromatin state characteristic of more differentiated, non-clonogenic,
and therapeutically vulnerable cells. By testing whether the balance between H3K27 histone methyltransferase
and demethylase activities can determine malignant transformation and the therapeutic response, these studies
could shed light on the mechanisms of brain tumorigenesis and lead to the development of novel therapeutics
targeting brain tumor epigenetics and histone dysregulation.

2013 Research Supported by the Cancer Frontier Fund at the Siteman Cancer Center Through The Foundation for Barnes-Jewish Hospital

Project: Patient-specific mutation-directed immunotherapy for melanomaPrinciple Investigator: Gerald Linette, MD, PhD; Co-investigator: Beatriz Carreno, PhD; Elaine Mardis, PhD
Summary: Goal is to create a personalized vaccine to activate the immune system to fight melanoma.
Description: The incidence of malignant melanoma (skin cancer) continues to rise worldwide. Metastatic melanoma remains an incurable cancer and novel treatments are urgently needed. The good news is recent advances with immunotherapy-which triggers the body's own immune system to fight cancer-suggest that lasting remissions are possible.

Mutations, or alterations in the DNA, due to sunlight exposure accumulate over time and promote the transformation of benign pigmented moles to malignant melanoma. Dr. Linette's research team believes that the immune system has the ability to recognize the sunlight-induced cell alterations as foreign and mount an immune response to attack the melanoma. The research project will analyze the melanoma genomes of five patients and identify mutations that are unique to each individual. Using these specific mutations, researchers will develop a customized cellular therapy vaccine to treat patients with advanced melanoma.

Project: Epigenetic Modulation of GvHD and GvLPrinciple Investigator: John F. DiPersio, MD, PhD; Co-investigators: Jaebok Choi, PhD; Mark Schroeder, MD
Summary: Goal is to determine if a drug, given just after bone marrow transplant, can potentially reduce a painful, life-threatening side effect.
Description: Cancers affecting the blood, bone marrow and lymph nodes-such as leukemia-remain a significant public health problem, accounting for about 10 percent of new cancer diagnoses. The good news is patients with these types of cancers can often be cured by bone marrow transplants. One type of cell in the donated transplant is a white blood cell (lymphocyte) called a T cell. As part of the immune system, T cells are the primary leukemia-fighting cells. However, in about 40 percent of cases, the donated T cells sometimes become overzealous and also attack the patient's skin, intestines, liver, and mucosa. This very painful and sometimes fatal condition is known as Graft versus Host Disease (GvHD). It affects nearly 50 percent of patients who have had a bone marrow transplant.

In Dr. DiPersio's study, he and his team are exploring whether acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) patients who receive bone marrow transplants experience less GvHD when given azacytidine, a drug already approved by the FDA for other purposes. In previous studies, the drug was shown to alter T cells so they retained their ability to attack the leukemia cells, but substantially reduced their undesired GvHD effect-sometimes totally eliminating it. This could be a significant step forward in cancer care. The hope is that this simple approach will reduce rates of GvHD after transplant and improve survival and quality of life after transplant.

Project: Role of Notch Signaling in AIDS-Associated Kaposi's SarcomaPrinciple Investigator: Lee Ratner, MD, PhD
Summary: Goal is to determine if a certain class of drugs is effective in treating Kaposi's Sarcoma and possibly other cancers.
Description: Dr. Ratner is launching a unique clinical study of AIDS-associated Kaposi's Sarcoma (KS). KS is an incurable tumor that often involves the skin, lungs, and gastrointestinal tract of patients with AIDS (acquired immunodeficiency syndrome) or other immunosuppressed conditions. KS is also found in elderly men in the Mediterranean area and boys in central Africa. The tumor is caused by the KS herpes virus (KSHV).

The Notch pathway is important for stem cells, development and new blood vessel formation. Mutations in Notch regulators appear frequently in a wide range of cancers; the Notch pathway can feed cancer growth. Drugs, known as gamma secretase inhibitors (GSI), have been developed to block Notch. In tissue culture studies, GSIs cause KS cell death.

Dr. Ratner's project is one of the first studies of any GSI to treat a specific form of cancer, i.e. KS. The next steps are for Dr. Ratner to work with patients to assess tolerance and response of KS to GSI; to determine whether levels of Notch regulators and Notch target genes are major determinants of how the cancer responds to the GSIs; and to determine which KSHV proteins are expressed in each patient's tumor and whether a specific pattern of protein expression predicts how the cancer responds. In addition, the study will determine what role new blood vessel formation plays in how GSIs work.

The outcome of this study could lead to new treatment for KS and could provide new information about the use of GSIs in other cancers.

Project: Phase 1B Clinical Trial of a Candidate Breast Cancer Prevention VaccinePrinciple Investigator: William Gillanders, MD; Co-investigators: Timothy Fleming, PhD; Simon Goedegebuure, PhD; Feng Gao, MD, PhD; A. Craig Lockhart, MD; Foluso Ademuyiwa, MD; David Denardo, PhD
Summary: Goal is to advance the development of a vaccine with the potential to prevent breast cancer.
Description: Cancer vaccines have generated considerable enthusiasm because of their tremendous potential for cancer prevention. Dr. Gillanders and his team have identified mammaglobin-A, a breast cancer-associated protein, as an excellent target for vaccine therapy. Mammaglobin-A is expressed in almost all breast cancers, and can potently stimulate the immune system. Thus, a mammaglobin-A vaccine would have significant potential for breast cancer prevention.

Through the study, Dr. Gillanders and his team will gain additional information about the vaccine's safety, assess the vaccine's ability to induce an immune response, and help optimize the vaccine's effectiveness against breast cancer. This study will significantly advance the clinical development of this innovative mammaglobin-A DNA vaccine.

Project: Development of a Multigene Assay for Predicting Oral Cancer MetastasisPrinciple Investigator: Ravindra Uppaluri, MD, PhD; Co-investigators: James Lewis Jr., MD; Michael Onken, PhD
Summary: Goal is to develop a genetic test for individual oral cancer patients that helps doctors prevent overtreatment by tailoring aggressive therapy only for those who need it.
Description: Oral cavity squamous cell carcinoma (OCSCC), a form of oral cancer, is a global health problem. More than 27,000 people are diagnosed each year in the United States alone. Unfortunately, early stage oral cancer is not always properly assessed, which can lead to overtreatment with surgery or radiation. Those treatments can lead to higher costs as well as more complications.

When OCSCC patients are first seen, treating physicians must decide whether the cancer has spread from the mouth to neck lymph nodes. Cancer that has spread to lymph nodes has a poorer prognosis because it may mean cancer can recur after treatment or has spread throughout the body. However, even if there are no obvious signs that cancer is in the lymph nodes, some surgeons prophylactically remove most of the lymph nodes in the neck prophylactically anyway. Unfortunately, this is an unnecessary operation in 70 to 80 percent of these patients and is associated with extended hospital stays, financial burden and surgical complications, including weakness in the shoulder due to nerve damage.

Dr. Uppaluri is studying the genetic signature of aggressive oral cancer tumors to predict which cancers are more likely to spread. If the study proves that the genetic predictor tests are as accurate as the pathology information provided by removing neck lymph nodes, then the test could be used to screen patients for metastatic disease without subjecting them to neck surgery.

The data collected from this study will support the development of the genetic test to reduce unnecessary surgery and provide patients with important information about their prognosis, such as whether the tumor is aggressive or likely to spread.

Project: Immune Based Therapies for AMLPrinciple Investigator: John F. DiPersio, MD; Co-investigators: Daniel Link, MD; Todd Fehniger, MD, PhD; William Frazier, PhD; Geoffrey Uy, MD; Reid Townsend, PhD; Michael Rettig, PhD; Rizwan Romee, MD
Summary: Goal is to find new avenues to treat leukemia by activating the patient's own immune cells.
Description: Through this study, Dr. DiPersio and his team will develop and test novel immune based therapies and cellular therapies to treat acute myelogenous leukemia (AML). About 60 to 80 percent of patients with AML will either relapse or have disease that doesn't respond to initial chemotherapy. Unfortunately, novel chemotherapy drugs have not improved patient outcomes and no new agents have been approved for AML since 1990.

Stem cell transplantation is one treatment approach to AML but it comes with some significant, treatment-related risks that can affect quality of life or even be life-threatening. Targeted immunotherapy represents a promising avenue for improving the outcomes of patients with AML.

Dr. DiPersio's team is tackling AML through a three-pronged approach. First, they will generate and test small proteins derived from antibodies that target unique antigens expressed or overexpressed on AML cells compared to normal cells. They will also modify and optimize these proteins so that natural killer (NK) and other cancer-fighting cells, in addition to T cells (the primary leukemia-fighting cells), more effectively kill the AML cancer cells.

In another trial, the team will test a new class of NK cells for their ability to kill AML cells. Finally, they will attempt to identify antigens on AML cells for the future development of targeting agents that engage other immune cells to attack cancer cells.

These novel therapeutic approaches show promise to be profoundly effective in AML, a disease for which therapy has not changed for more than 40 years. The discoveries made in these projects will pave the way for development of additional agents and approaches to treat other blood and solid tumor cancers.

Project: Tamoxifen to Treat Barrett's MetaplasiaPrinciple Investigator: A. Craig Lockhart, MD; Co-investigators: Jean Wang, MD, PhD; Jason Mills, MD, PhD; Yan Yan, MD, PhD
Summary: Goal is to determine if a current hormonal therapy drug can prevent esophageal cancer.
Description: Barrett's esophagus (BE) is a condition in which the cells of the lower esophagus become damaged. This is usually caused by repeated exposure to stomach acid from acid reflux. Barrett's esophagus has no current treatment and can lead to esophageal cancer.

Dr. Lockhart's research aims to prevent cancer from forming by treating patients with Barrett's esophagus with tamoxifen, an established hormonal therapy, to determine whether the drug can reverse some of the molecular changes associated with this condition. Tamoxifen is already a well-studied drug with few side effects. If this treatment strategy proves successful, this could represent a new treatment approach for patients with Barrett's esophagus-and even prevent esophageal cancer. In addition, repurposing an already approved cancer drug as a cancer preventative can shorten the time needed to bring a new therapy to use in patients.

The Children's Discovery Institute at St. Louis Children's Hospital Awards

Project: Functional Characterization of Rare Congenital Variation in Infantile Leukemia (IL)Principle Investigator: Todd Druley, M.D., Ph.D.
Description: Infant leukemia (IL) remains the deadliest of all pediatric leukemias, with a survival rate of less than 50%. Dr. Druley found that IL patients are born with a significant enrichment of rare and damaging genetic variants in leukemia-associated genes. Every infant with acute myeloid leukemia (AML) inherited damaging MLL3 gene variants from each parent, suggesting that, in a specific genomic context, infant AML requires dysfunction of MLL3.
Potential Impact: The use of genomics as a discovery tool for IL could lead to new insights into how inherited genetic variation influences complex disease. Moreover, this research could enable testing of novel therapeutic agents and lead to new strategies for engineering blood stem cells that could be transplanted into IL patients, ultimately improving clinical outcomes.

Project: The Developmental Changes in Stem Cell Self-renewal Mechanisms and Their Role in LeukemogenesisPrinciple Investigator: Jeffrey Magee, M.D.
Description: Leukemia is the most common pediatric cancer, and it is among the most common causes of disease-related death in children. We are interested in understanding how mutations in blood-forming stem cells cause leukemia. We have shown that a mutation that increases stem cell numbers and causes rapid leukemia development at one stage of life may be relatively benign at another. We are working to understand how and why certain mutations have age-dependent effects on stem cells and evolving leukemia cells.
Potential Impact: Our overarching goal is to develop strategies to more precisely and effectively treat childhood leukemia.

Project: Nextgen Deep Sequencing In Post-transplant Lymphoproliferative Disorders (PTLD)Principle Investigator: Vikas Dharnidharka, M.D., Ph.D.
Description: Post-transplant lymphoproliferative disorder (PTLD) is a malignant transformation of white blood cells called lymphocytes that occurs in solid-organ or tissue-transplant recipients, resulting in significant morbidity and mortality. Many PTLD cases are caused by the Epstein-Barr virus (EBV), but the remaining cases have no known cause. The goal is to study the underlying causes and predictors of clinical outcomes in EBV-positive and EBV-negative PTLD cases. Newly available next-generation deep shotgun sequencing technologies through the Washington University Genome Institute will be used to simultaneously detect many different known viral sequences from extracted stored PTLD tissue paraffin blocks.
Potential Impact: This high-risk multidisciplinary project could have a major impact in the field, potentially revealing not only the causes of EBV-negative PTLD cases, but also genomic variants that could be studied for future therapeutic targets.

The Siteman Cancer Center Individual and Team Awards

Project: Defining Molecular Targets on Micro Metastatic Disease in Breast CancerPrinciple Investigators: Dr. Rebecca Aft and Dr. Mark Watson
Description: Metastasis is the most significant contributor to mortality in breast cancer patients. Data suggests that only a small subset of cells within the primary tumor possess metastatic potential. Dr. Aft hopes to develop a molecular "signature" for this subset of cells that will reveal their presence, gauge their metastatic potential, and provide guidance on systemic therapy. Her findings lead to the development of a standardized test to guide targeted therapy directed against micro-metastatic disease. The successful completion of this study would significantly alter the therapeutic management of breast cancer patients based on the presence, classification, and variations in metastasizing tumor cells.

Project: Epigenetic Modulation of GvHD and GvLPrinciple Investigator: Dr. John DiPersio
Description: In an attempt to ward off relapse of certain diseases, such as leukemia, some patients receive a bone marrow transplant. While this approach can be curative, 50% of all bone marrow transplant patients eventually develop Graft vs. Host Disease (GvHD), a life threatening complication. In GvHD, the donor T-cells attack not only the patient's cancer cells but other healthy cells as well. Although stem cell transplantation represents the best and most effective approach to cure patients with leukemia, pre-leukemia, lymphoma and other conditions adversely affecting bone marrow function, it is also the most risky. The "holy grail" for stem cell transplantation researchers is to eliminate GvHD while maintaining a potent graft vs. cancer effect. Building on previous findings, Dr. DiPersio will conduct a clinical trial to determine if azacitidine, administered shortly after transplant, can suppress or eliminate GvHD without impairing the curative potential of the transplanted T-cells. This study may offer opportunities to reduce life-threatening toxicities of stem cell transplantation; and to permit use of mismatched donors, thus opening up this potentially curative treatment to all patients.

Project: Patient-specific mutation-directed immunotherapy for melanomaPrinciple Investigator: Dr. Gerry Linette
Description: Despite recent treatment advances, metastatic melanoma remains an incurable malignancy with an expected survival of 12 to 14 months. Investigational cancer vaccines as well as adoptive T cell therapies are now beginning to show efficacy in early phase clinical trials. However, a critical barrier facing investigators developing these cellular therapies is the limited number of validated melanoma (tumor) antigens that can be use to activate a patient's T cell immune system. By coupling gene sequencing with laboratory testing, Dr. Linette and collaborators at the Genome Institute plan to develop genomics-guided tumor antigen identification for incorporation in vaccines that are unique to each patient's tumor. This study may delineate a "road-map" for development of personalized cellular therapies for the treatment of advanced melanoma.

Project: Exploring mechanisms to treatment resistance to improve outcomes in pancreatic cancerPrinciple Investigators: Drs. David Linehan, David Denardo, Andrea Wang-Gillam, Jason Weber, William Hawkins, and Dirk Spitzer
Description: Pancreatic cancer is highly resistant to chemotherapy; consequently, patient survival rates are extremely low, less than 3%. With 2011 Cancer Frontier Fund support, team members worked to determine why pancreatic cancer is so resistant to chemotherapy. The initial investigations yielded significant findings, which led to a clinical trial and a second year of funding from the Cancer Frontier Fund to continue this promising line of research. Researchers identified new therapeutic targets and disease biomarkers linked to patient survival as well as treatment resistance. By understanding how cancer cells evade chemotherapy, researchers can develop more effective strategies to overcome this resistance and improve patient outcomes.

Project: Identifying Mechanisms of Metastasis to Improve Outcomes in Metastatic Colorectal CancerPrinciple Investigators: Dr. Ryan C. Fields, Dr. Peter Goedegebuure, Dr. A. Craig Lockhart, Dr. Christopher Maher Elaine Mardis, and Dr. Richard K. Wilson
Description: Little is known about the biology in the genetic progression from primary tumor to metastatic disease (mCRC) in colorectal cancer. To address the unmet clinical need of better treatments for colorectal cancer that has spread, this study will conduct an advanced genetic and epigenetic analysis of matched tissue samples (i.e. from the same patient) from primary and mCRC tumor specimens in hopes of identifying novel therapeutic targets. This "team science" effort consists of four overlapping projects that investigate specific aspects of metastatic tumor biology to gain a clearer understanding of the pathways by which primary tumors gain the ability to metastasize. This project represents a unique and incredible opportunity in the field of genomics for colorectal cancer and will lay the foundation for future and continued multidisciplinary applications.

Project: Using Heat Ablation to Disrupt the Blood Brain Barrier to Enhance Delivery of Chemotherapy in the Treatment of Recurrent GlioblastomaPrinciple Investigators: Dr. David Tran, Dr. Eric Leuthardt, and Dr. Joshua Shimony
Description: Glioblastoma multiforme (GBM) is the deadliest high-grade malignant brain tumor in adults. Combined radiation and chemotherapy produces only a small survival benefit, with most patients dying within five years. One challenge to treatment is the inability of available drugs to pass the blood-brain barrier, a mechanism that protects the central nervous system by creating a barrier between brain tissues and circulating blood. This study will investigate whether laser heat ablation guided by brain MRI is effective in temporarily disrupting the blood-brain barrier, thereby facilitating penetration of drugs into the tumor and the surrounding area, and improving patient response to treatment. If proven effective, this approach will increase the number of drugs that could be used for successful treatment of GBM and could also be applied to treatments of other primary brain tumors and brain metastases.

The Children's Discovery Institute at St. Louis Children's Hospital Awards

Project: Altered Epigenetics as a Driver of T-cell Acute Lymphoblastic LeukemiaPrinciple Investigator: Dr. Grant Challen
Description: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. A subgroup with T-cell ALL (T-ALL) have a poor prognosis. DNA methylation is an "epigenetic" modification that does not alter the DNA sequence, but produces marks or "flags" on DNA that can turn genes on or off. Cancer cells exhibit an altered pattern of these methylation flags. As mutations in DNMT3A, an enzyme that establishes methylation flags, have been discovered in T-ALL patients, we propose that DNMT3A mutations predispose T-cells to become cancerous. We have shown that mice lacking Dnmt3a are more susceptible to T-ALL development. Moreover, immature T-cells in the thymus of mice lacking Dnmt3a have an overactive pathway called Notch. These studies will investigate the links between Dnmt3a-mediated DNA methylation, Notch, and ALL. The long-term goal of this project is to help develop treatments and improve the outcomes for patients with acute lymphoblastic leukemia, the most common cancer in children.

Project: Targeting Nucleolar Protein Interactions in Pediatric GliomasPrinciple Investigators: Dr. Jason Weber, Dr. Jeffrey Leonard
Description: Gliomas are one of the most common brain tumors in children. The survival rate for patients with a high-grade form of these tumors is less than one year. This project will investigate the role of two proteins located in the brain - nucleolin (NCL) and nucleophosmin (NPM) - in the development of gliomas. That will help establish whether to target these proteins in treating these tumors. Potential impact of the project: We will identify whether NCL, NPM and their interactions are important for glioma tumor cell growth and survival, and could be potential anti-cancer targets for treating pediatric gliomas.

The Siteman Cancer Center Individual and Team Awards

Project: Exploring mechanisms of treatment resistance to improve outcomes in pancreas cancerPrinciple Investigators: David C. Linehan, MD; Davide DeNardo, PhD
Description: Almost all patients that develop pancreatic cancer require chemotherapy, yet it is highly resistant to treatment and has a median survival of only 4-6 months. This project will study biologic mechanisms behind this resistance and devise novel strategies to overcome this. Three distinct hypotheses will be pursued, each probing a mechanism of therapeutic resistance and a novel therapeutic approach. All these aspects will be combined to understand how the various mechanisms are integrated. This will also guide the development of strategies to improve the response to treatment, and help identify patients likely to benefit from the therapies.

Project: Investigations of HER2 Mutation in HER2 Negative Breast CancerPrinciple Investigator: Cynthia Ma, MD
Description: In patients with HER2 positive breast cancer, anti-HER2 drugs, including trastuzumab (Herceptin) and lapatinib (Tykerb), are readily available and used with good results. However, these drugs are not FDA-approved for HER2 negative breast cancer. This project seeks to establish that this subset of HER2 negative patients can be effectively treated with anti-HER2 agents. If successful, the results will lead to larger trials and, some day, treatment access for all patients with this cancer to the increasing numbers of anti-HER2 medications.

Project: Validation of Biomarkers for Kidney Cancer Diagnosis and Monitoring of Metastatic DiseasePrinciple Investigator: Jeremiah Morrissey, PhD
Description: When diagnosed by symptoms, patients with the two predominant forms of kidney cancer (clear cell and papillary) have poor outcomes. When caught earlier, patient survival rates exceed 70%. There is currently no method of screening for kidney cancer and tumors are usually discovered due to other medical investigations. The team will screen large groups of patients to determine if certain biomarkers can correctly identify and predict cancerous tumors and their metastasis to other parts of the body. Success will result in a clinically applicable, first-ever method for early diagnosis of kidney cancer, moving rapidly toward approval for commercial production.

Project: Human Cancer Immunotherapy Targeting Tumor-Specific Mutational Antigens Identified by Exome SequencingPrinciple Investigator: Robert Schreiber, PhD
Description: Recently, members of this team found that cancer genome sequencing can rapidly identify expressed mutations in tumors and showed that some can function as tumor-specific antigens. These mutations target the tumor for immune elimination. This study seeks to extend and validate this novel observation, through new genome sequencing and with attention to the identification of involved proteins. The goal is to develop a method to rapidly and reliably identify the tumor-specific antigens that most effectively induce immune system destruction of tumors.

Project: Targeting the Bone Marrow Environment in Multiple MyelomaPrinciple Investigator: Daniel C. Link, MD
Description: In this research, an exciting new therapy will be tested based on a surprising observation made in the Link laboratory. A small clinical trial will determine if treating with G-CSF before starting chemotherapy improves the response rate in patients with multiple myeloma. This research may have applications for other blood cell cancers, such as certain types of acute leukemia.

Project: Neurobiology of Chemotherapy-Induced Cognitive ImpairmentPrinciple Investigator: Jay F. Piccirillo, MD, FACS
Description: Chemotherapy-induced cognitive impairment, or "chemobrain," may affect as many as 50% of breast cancer patients. The neural mechanisms in the brain that are responsible for chemobrain are unknown. A novel imaging technique at Washington University, known as resting-state functional connectivity magnetic resonance imaging, measures the functional circuitry or connections between brain regions involved in a particular function. Successful completion of this study will translate basic mechanisms of brain function to chemobrain research, thereby helping to advance the field of cancer survivorship and behavioral research.

Project: Understanding the Mechanism of BRAF Inhibitors in the Induction of Squamous Cell CarcinomaPrinciple Investigator: Audrey S. Shaw, MD
Description: Vemurafenib is a new drug recently approved by the FDA for the treatment of melanoma. While this drug has a dramatic effect on melanoma growth, in a large fraction of patients it causes squamous cell carcinoma to develop. This side effect severely limits the effectiveness of the drug treatment. This project proposes to use genome sequencing to understand why vemurafenib causes squamous cell tumors. It is hoped that this will help develop better drugs for the treatment of melanoma.

Project: MicroRNA Expression Signatures to Predict Cervical Cancer OutcomePrinciple Investigator: Xiaowei Wang, PhD
Description: Invasive cervical cancer is the second most common cancer in women worldwide, resulting in over 300,000 deaths each year. This study focuses on discovering new molecular biomarkers (or, indicators in the body of stress, injury or other change in normal functioning due to disease or the environment) for early identification of cervical cancer patients who would fail standard therapy. In this way, potential individualized therapies can then be applied to these high-risk patients to improve treatment outcome.

The Children's Discovery Institute at St. Louis Children's Hospital Awards

Project: Targeting An RNA Surveillance Pathway In Pediatric CancerPrinciple Investigators: Zhongsheng You, Ph.D.; Divid Piwnica-Worms, M.D., Ph.D.
Description: Cancer is mainly caused by mutations in DNA, which either turn expression of genes on or off or generate protein products with abnormal functions. Nonsense-mediated messenger RNA decay (NMD) is a surveillance system that detects and eliminates defective messenger RNAs that would otherwise produce truncated protein products. Identification of NMD defects in pediatric brain tumors will provide new insights into the underlying molecular defects leading to brain tumors and new potential therapeutic targets. Possible therapies for abnormal NMD may be identified by the small molecule inhibitor screens and studies on NMD pathway genes.

Project: Sexually Dimorphic cAMP Signaling Impacts the Rate of Brain Tumors in Prepubertal Boys & GirlsPrinciple Investigators: Joshua Rubin, M.D., Ph.D.; David Gutmann, M.D., Ph.D.
Description: Incomplete understanding of why children get brain tumors hinders their cure. Neurofibromatosis 1 (NF1) is the most common genetic disease associated with childhood brain tumors (gliomas). The goal of this project is to better understand why some children with NF1 get gliomas and others do not. To achieve this goal we will examine subtle variations in DNA known as polymorphisms. Success in these aims will improve diagnostics and therapeutics for children with brain cancer as early as the next 10 years.

Project: Investigation of Somatic Defects in Patients with Autoimmune DiseasesPrinciple Investigator: Megan Cooper, M.D., Ph.D.
Description: Pediatric autoimmune diseases such as systemic lupus erythematosus are often difficult to diagnose and can have devastating long-term effects on health including chronic arthritis organ damage cardiovascular disease, and mortality. This project will investigate whether pediatric patients with other autoimmune diseases that share clinical features of ALPS, including systemic lupus erythematosus and mixed connective tissue disease, have abnormal immune cells with somatic genetic defects. This research will lead to new approaches for diagnosis, monitoring, and treatment of these diseases within the next 10 years.

Project: Molecular Strategies to Block Peripheral Neuropathy in Mouse Models of Vincristine NeurotoxicityPrinciple Investigator: Martha Bhattacharya, Ph.D.
Description: Pediatric cancer patients are routinely prescribed chemotherapy including the drug vincristine. While vincristine is effective in disrupting cell division and halting tumor growth, it comes with the serious side effect of peripheral nerve damage. This damage can cause loss of motor and sensory function as well as intense pain. We have identified a number of critical molecular pathways used by vincristine and other chemotherapy drugs to cause axonal damage. This work will enhance our mechanistic understanding how peripheral neuropathy develops in pediatric and adult cancer patients following exposure to chemotherapy drug and how this can be prevented.

The Siteman Cancer Center Individual and Team Awards

Project: Role of XMRV Retrovirus Infection in Prostate CancerPrinciple Investigator: Lee Ratner, MD, PhD
Description: Ratner will investigate the role of a virus in the development of prostate cancer. His research has the potential to make strides toward new therapies for the treatment and prevention of prostate cancer.

Project: Molecular Predictors of Ductal Carcinoma In Situ Progression To Invasive Breast CancerPrinciple Investigator: Ron Bose, MD, PhD
Description: Between 20-25 percent of all newly diagnosed instances of breast cancers are ductal carcinoma in situ (DCIS), which are small and contained tumors. Standard treatment can be aggressive, with more side effects than necessary in cases where tumors would not have spread. Dr. Bose's goal is to determine which DCIS lesions are most likely to spread and invade other tissues, in order to treat those lesions specifically, which would result in better outcomes for patients with fewer side effects.

Project: Melanoma Management by in Vivo Laser-Induced Photoacoustic Microscopic ImagingPrinciple Investigator: Lynn Cornelius, MD
Description: In a unique collaboration, dermatologist Cornelius is working with biomedical engineer Wang to develop a handheld imaging device that will improve melanoma detection at an early stage (when surgery has the greatest chance of cure) and measure a tumor's depth and volume (a technology not currently available). Their goal is to bring this device to the bedside, where it may impact the survival of melanoma patients.

Project: Adolescent Diet and Risk of Proliferative Benign Breast DiseasePrinciple Investigator: Graham Colditz, MD, DrPH
Description: Diet during adolescence may have effects on such early indictors of breast cancer as rapidly-spreading benign breast disease, and also on some characteristics of normal appearing breast tissues. A study by Graham Colditz, MD, DrPH will measure these effects, and how changes in diet at this critical time in growth and development can reduce the likelihood of a person developing breast cancer.

Project: Characterization of the Stroma from Ductal Carcinoma in Situ and ProgressionPrinciple Investigator: Ying Liu, MD, PhD
Description: Dr. Liu's team will compare proteins expressed in pure ductal carcinoma in situ (DCIS) legions with those expressed in the components of DCIS associated with invasive breast cancer (IBC), for which DCIS can be a precursor. Their data will have profound implications for estimating an individual's risk of developing IBC and for targeting cancer intervention therapies for those patients.

Project: Breast Cancer Development in the FASST MousePrinciple Investigator: Shelia Stewart, PhD
Description: Cancer is not only the result of mutations within cancer cells, but also a result of age-related changes in the surrounding noncancer cells. Shelia Stewart, PhD and her team are working to uncover how older, noncancerous cells impact the development of breast cancer, with the goal of uncovering targets for therapy within the noncancerous cells because they are less likely to be resistant to therapies than the tumor itself. This research will ultimately impact the development of anti-cancer drugs.

Project: Prediction of Response to Endocrine Therapy in Premenopausal Women with FFNP-PET Imaging and PEPIPrinciple Investigator: Farrokh Dehdashti, MD
Description: Patients with hormone sensitive, operable breast tumors are often treated with endocrine therapy (a type of hormone therapy) to shrink the tumor. However, only slightly more than 50 percent of patients who receive this therapy respond to it. Farrokh Dehdashti, MD and her team will use existing imaging technology in a novel way to more accurately predict which patients will most likely respond to endocrine therapy, and which patients will not, to ultimately improve personalized treatment plans for breast cancer patients.

Project: Role of Notch-EGFR pathway cooperativeity in basal-like breast cancerPrinciple Investigator: Loren Michel, MD
Description: Basal-like breast cancer is a highly lethal form of the disease, and effective therapies are lacking. Loren Michel, MD and his team will study how blocking two specific receptors (structures on a cell that receive and bind it to substances) may effectively kill basal-like breast cancer cells. Their study will lay the foundation for a clinical trial of a new treatment option for basal-like breast cancer.

Project: Characterization of the Stroma from Ductal Carcinoma in Situ and ProgressionPrinciple Investigator: Ying Liu, MD, PhD
Description: Dr. Liu's team will compare proteins expressed in pure ductal carcinoma in situ (DCIS) legions with those expressed in the components of DCIS associated with invasive breast cancer (IBC), for which DCIS can be a precursor. Their data will have profound implications for estimating an individual's risk of developing IBC and for targeting cancer intervention therapies for those patients.

Project: Imaging Biomarkers for Radiation-Induced NecrosisPrinciple Investigator: Joel Garbow, PhD
Description: Radiation therapy is an important part of treatment for patients with brain tumors. However, radiation necrosis (a severe type of injury to normal, healthy brain tissue that occurs several months following radiation treatment) can negatively impact a patient's life-and distinguishing necrosis from a recurrent tumor is a significant challenge. Both issues have critical consequences for patient treatment and outcomes. Joel Garbow, PhD and his team will develop magnetic resonance imaging (MRI) tools and use experimental MRI techniques to clarify the understanding of the brain tissue changes that follow radiation therapy of the brain. The ability to monitor these changes non-invasively, and to prevent and reduce these changes with therapeutic interventions, will lead to better clinical outcomes and improved quality of life for patients with brain tumors.

The Children's Discovery Institute at St. Louis Children's Hospital Awards

Project: Characterization of the Brain Tumor Microenvironment ProteomePrinciple Investigator: Joshua Rubin, MD, PhD
Description: The investigators will determine how the presence of a brain tumor changes the brain around it and what the differences are in the response to a brain tumor between different regions of the brain. Defining these differences will extend understanding of this critical mechanism for the regulation of brain tumor growth and will identify targets for a novel approach to brain tumor therapy that addresses the functions of the surrounding brain rather than the tumor itself.

Project: Why Do Children Get Cancer?Principle Investigators: Todd Druley, MD, PhD and Robi Mitra, PhD
Description: Druley and Mitra have begun the enormous task of developing a way to find and quantify all of the alternative forms of a given gene - even those that occur in less than one percent of humans. The new tools the team developed will help identify a variety of rare, but important genetic variants related to the disease and help to answer the question of why children get cancer.